Chronic urticaria (CU) is a common, debilitating, relapsing dermatological disorder characterized by daily hives for at least 6 weeks, and in many individuals, lasting over 20 years. The course of CU, and response to treatment, is highly unpredictable and heterogeneous. Mechanisms contributing to the onset and recurrence of most cases of CU are unknown. Considerable evidence suggests an association between chronic psychological stress and CU. Our overall hypothesis is that CU is associated with chronic stress and blunted neuroendocrine stress response systems including hypothalamic-pituitary-adrenal (HPA) and sympathetic- adrenomedullary (SAM) axes, and that attenuated HPA and SAM function mediates the link between stress and activation of dermal inflammation. This proposal focuses on the systematic investigation of central HPA and SAM function in adults with CU. HPA and SAM basal activity will be assessed over 3 days to characterize diurnal patterns. HPA and SAM acute reactivity will be elicited with a highly standardized, laboratory stress induction paradigm (Trier Social Stress Test Booth); serial venous sampling will be obtained before and after the TSST for HPA and SAM bio-mediators. Standardized measures will also ascertain life stressors, psychological stress vulnerability, and CU severity. Specific Aims: 1) to investigate HPA and SAM basal activity in adults with CU compared to controls, 2) to investigate HPA and SAM acute reactivity to a psychosocial stressor, compared to controls, and 3) to explore differences in stress vulnerability variables between groups, and the relationship of these variables to HPA and SAM function. The proposal has high impact in moving the field forward in investigating specific mechanisms underlying the link between stress and CU to inform the subsequent development of novel, stress-specific treatments and preventive interventions for CU. PUBLIC HEALTH RELEVANCE: This study systematically investigates biological stress system [hypothalamic-pituitary-adrenal (HPA) and sympathetic-adrenomedullary (SAM)] dysfunction in adults with chronic urticaria (CU) as a potential mechanism linking chronic psychological stress and recurrent hives. The study has high public health significance in identifying potential stress-specific targets for the development of novel treatment and prevention interventions for CU.